The research in my laboratory is focused on identifying novel prostate-specific genes, defining their regulation and function, and utilizing the knowledge to prevent and treat prostate diseases. We employed the lineage-related human prostate cancer (PCa) cell lines, LNCaP and C4-2, as a PCa progression model to uncover genes with increased representation during PCa progression. In this proposed study, we will elucidate the function of PrLZ (Prostate Leucine Zipper), a novel, prostate-specific, and androgen-responsive gene, isolated by my laboratory. The PrLZ gene is localized at chromosome 8q21.1, within a locus most frequently amplified in human PCa. It is the only prostate-specific gene identified in the 8q21 amplicon. Our data demonstrated that the expression of PrLZ correlated to proliferative activity of the prostate epithelium, while its abnormally enhanced expression was an early marker for PCa. Over-expression of PrLZ promoted growth of the PCa cell lines in vitro and tumors in vivo, and enhanced the expression of midkine, an important growth factor in tumorigenesis. PrLZ may interact with certain 14-3-3 proteins and the interaction may modulate the PrLZ function. With these characteristics, PrLZ appears to be a novel marker for PCa diagnosis and a potential therapeutic target for PCa. Specific aims of this proposal are: Aim 1. To determine the causal relationship between PrLZ expression and PCa progression using the LNCaP PCa progression model. Since PrLZ may confer increased PCa growth and metastasis, we will change the level of PrLZ expression in the PCa progression model to confirm the oncogenic function of the PrLZ. Aim 2. To characterize PrLZ isoforms and to determine their interaction with 14-3-3 proteins. Because certain 14-3-3 isoform may modulate the oncogenic function of the PrLZ, we will first identify the isoform, and then determine the tumor suppressive property of this isoform. Aim 3. To define midkine as a downstream target gene of the PrLZ. PrLZ may promote proliferation by enhancing midkine expression. We will develop an inducible system to determine the relationship between PrLZ and midkine expression.